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Comparative responsiveness of HL-60, HL-60R, and HL-60R+ (LRARSN) cells to
retinoic acid, calcitriol, 9 cis-retinoic acid, and sodium butyrate
KB Atkins and BR Troen
Department of Internal Medicine, Veterans Administration Medical Center,
Ann Arbor, MI, USA.
In HL-60 cells, retinoic acid (RA) and 9 cis-RA induce granulocytic
differentiation, and calcitriol and sodium butyrate induce monocytic
differentiation. To study the role of retinoid resistance on the response
to these agents, we investigated their effects in HL-60 cells,
retinoid-resistant HL-60R cells, and HL-60R+ cells in which retinoid
sensitivity has been restored. In HL-60 cells, cathepsin D (ctsd) mRNA
levels are increased by these agents and by cholera toxin after
pretreatment with each agent. Calcitriol, 9 cis-RA, and sodium butyrate
increase interleukin-8 (IL-8) mRNA expression, and pretreatment with these
agents or RA potentiates the stimulation of IL-8 by phorbol ester (TPA).
Pretreatment of HL-60 cells with all of the agents confers inducibility of
cathepsin L (ctsl) mRNA by TPA in previously unresponsive cells. In HL-60R
cells, none of the agents alone or in combination significantly enhances
the expression of the ctsd, IL-8, or ctsl mRNAs. Retinoid stimulation
(either alone or in combination with the other agents) of the three mRNAs
is partially restored in the HL- 60R+ cells. Calcitriol does not alter the
expression of any of these mRNAs, and only the stimulation of IL-8 mRNA by
sodium butyrate is recovered. Treatment with all of the agents inhibits
proliferation and stimulates differentiation of the HL-60 cells. RA and
calcitriol are unable to inhibit proliferation of the HL-60R cells, whereas
only calcitriol fails to inhibit proliferation of the HL-60R+ cells. None
of the agents induces differentiation in either the HL-60R or HL-60R+
cells. Therefore, the mutation of the RA receptor alpha is insufficient to
account for the altered responses of the HL-60R cells, and there are likely
defects in other signaling pathways in these cells. These cells may prove
useful in examining the mechanism of cross-resistance between various
differentiating agents.
Volume 86,
Issue 7,
pp. 2475-2480,
10/01/1995
Copyright © 1995 by The American Society of Hematology

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